The Heterozygous P.R76W Hnf4A Variant Is Associated with Atypical Autosomal Dominant De Toni-Fanconi-Debré Syndrome and Can Be Diagnosed Utilising Diagnostic Clinical Exomic Analysis

Aim: To identify a rare genetic cause for atypical autosomal dominant Fanconi renotubulopathy mimicking Dent’s Disease amongst Australian patients.
Background: The HNF4A gene is associated with “Maturity Onset Diabetes of the Young Type 1” however a specific variant has recently been identified causing distinctive autosomal dominant renal tubulopathy. Translation to clinical diagnostic sequencing is desirable.
Methods: Two Australian patients with atypical Fanconi renotubulopathy respectively underwent small-pedigree whole exomic sequencing (WES) and diagnostic clinical exome sequencing via the Australian Renal Genetic Disorders Panels (ARGP) at Westmead.
Results: Patient 1 presented at 10 years with rickets (requiring multi-level orthopaedic procedures), short stature, asymptomatic low-molecular-weight proteinuria with Fanconi renotubulopathy and progressive chronic kidney disease(CKD). Development was otherwise normal with past history of surgically repaired ventricular septal defect at 5 years. Growth hormone therapy precipitated diabetes mellitus, which resolved upon its cessation. Renal biopsy, imaging and CLCN5/OCRL were normal. Small-pedigree WES identified the de novop.R76W (NM_000457.4): c.[187C>T];[=]) variant in HNF4A. Patient 2 presented in early childhood with asymptomatic low-molecular-weight proteinuria. She progressively developed Fanconi renotubulopathy, progressive CKD, recurrent morning ketotic hypoglycaemia, hyperaldosteronism, minor osteopenia, subclinical rickets, intermittently raised intraocular pressure, hypermetropia, mild intellectual impairment, generalised joint hypermobility, and pancreatic hyperechogenicity of unknown cause. Renal biopsy, imaging and CLCN5 were normal. ARGP analysis was initially negative, however reanalysis based on recent reports of patients with the p.R76W variant in HNF4A, identified this variant(NM_000457.4):c.[187C>T][=]).Conclusions: These cases reconfirm the association of this heterozygous variant in HNF4A with atypical Fanconi renotubulopathy whilst demonstrating diagnostic translation and integration into the clinical ARGP service for identification of further cases. Further research into the pathogenic mechanism of this variant is required.